Derivatives of imidazo[2,1-b] thiazole

ABSTRACT

Compounds of the formula: ##STR1## and pharmaceutically acceptable acid addition salts thereof wherein R, R 1 , R 2 , R 3 , are selected from the group consisting of hydrogen, halogen and lower-alkyl of from one to four carbon atoms, inclusive; with the proviso that taken together they constitute the following substituents on the tetracydic ring, 10-halo, 8,10-dihalo, 8,9-di-lower-alkyl, and 7,9-dilower-alkyl; R&#39;, R&#39; 1 , R&#39; 2 , and R&#39; 3  are selected from the group consisting of hydrogen, halogen and lower alkyl of from one to four carbon atoms, inclusive, with the proviso that when taken together they constitute the following substituents, 1-halo, 2-halo, 3-halo, 4-halo, 1-lower-alkyl, 2-lower-alkyl, 3-lower-alkyl, 4-lower-alkyl, 1,3-dihalo, 2,3-dihalo, 2,4-dihalo, 3,4-dihalo, 1,3-di-lower-alkyl, 2,3-di-lower-alkyl, 1,4-di-lower-alkyl; R 4 , R 5 , R 6 , and R 7  are selected from the group consisting of hydrogen, halogen and lower-alkyl of from one to four carbon atoms, inclusive, with the proviso that when taken together they constitute the following substituents on the tetracyclic ring, 9-halo, 8-halo, 7-halo, 6-halo, 9-lower-alkyl, 8-lower-alkyl, 7-lower-alkyl, 6-lower-alkyl, 7,9-dihalo, 7,8-dihalo, 6,8,-dihalo, 6,7-dihalo, 79-di-lower-alkyl, 7,9-di-lower-alkyl, 7,8-di-lower-alkyl, and 4,6-di-lower-alkyl. R 8  is selected from the group consisting of hydrogen, lower-alkyl of from one to four carbon atoms, inclusive, and R 9  is selected from the group consisting of hydrogen and halo. These compounds are useful as anti-hypertensive agents in mammals.

This is a division of application Ser. No. 857,854, filed Dec. 5, 1977,now U.S. Pat. No. 4,160,840, which is a continuation of application Ser.No. 726,390, filed Sept. 24, 1976, now abandoned.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The invention concerns novel imidazoindole derivatives andpharmaceutically acceptable acid addition salts thereof; compositionsprepared therefrom and methods of their use.

2. Description of the Prior Art

The compound 1,2,3,5-tetrahydroimidazo[2,1-b]quinazoline and some of itsderivatives with three-ring systems have structural similarity to ourcompounds with four ring systems and have been reported by Loev, et al.,Journal of Medicinal Chemistry, 15, 727 (1972) and Jen et al., Journalof Medicinal Chemistry. 15, 727 (1972) as effective antihypertensiveagent in animals. However, insofar as is presently known, no one hasprepared applicants imidazoindole derivatives.

SUMMARY OF THE INVENTION

This invention pertains to some new organic compounds, a process forpreparing them, pharmaceutical compositions containing them, and methodsof using them. The invention is more particularly directed toderivatives of imidazoindole, and pharmaceutically acceptable acidaddition salts thereof having the formula ##STR2## and pharmaceuticallyacceptable acid addition salts therof wherein R, R₁, R₂, R₃, areselected from the group consisting of hydrogen, halogen and lower-alkylof from one to four carbon atoms, inclusive; with the proviso that takentogether they constitute the following substituents on the tetracyclicring, 10-halo, 8,10-dihalo, 8,9-di-lower-alkyl, and 7,9-dilower-alkyl;R', R'₁, R'₂, and R'₃ are selected from the group consisting ofhydrogen, halogen and lower alkyl of from one to four carbon atoms,inclusive, with the proviso that when taken together they constitute thefollowing substituents on the tetracyclic ring, 1-halo, 2-halo, 3-halo,4-halo, 1-lower-alkyl, 2-lower-alkyl, 3-lower-alkyl, 4-lower-alkyl,1,3-dihalo, 2,3-dihalo, 2,4-dihalo, 3,4-dihalo, 1,3-di-lower-alkyl,2,3-di-lower-alkyl, 1,4-di-lower-alkyl; R₄, R₅, R₆, and R₇ are selectedfrom the group consisting of hydrogen, halogen and lower-alkyl of fromone to four carbon atoms, inclusive, with the proviso that when takentogether they constitute the following substituents on the tetracyclicring, 9-halo, 8-halo, 7-halo, 6-halo, 9-lower-alkyl, 8-lower-alkyl,7-lower-alkyl, 6-lower-alkyl, 7,9-dihalo, 7,8-dihalo, 6,8-dihalo,6,7-dihalo, 7,9-di-lower-alkyl, 7,8-di-lower-alkyl, and4,6-di-lower-alkyl. R₈ is selected from the group consisting ofhydrogen, lower-alkyl of from one to four carbon atoms, inclusive, andR₉ is selected from the group consisting of hydrogen and halo.

The invention also comprises pharmaceutical dosage unit forms adaptedfor systemic administration to obtain anti-hypertensive effects inmammals comprising an effective amount of a compound according toformulas I and Ia, or a pharmaceutically acceptable acid addition saltthereof, in combination with pharmaceutical means which adapt suchcompounds for systemic administration.

Further the invention relates to methods of treating hypertension inmammals, for example humans and valuable warm-blooded animals such aslaboratory rats, dogs, cats and other domestic animals by administeringsystemically to the mammals, the aforesaid pharmaceutical dosage unitforms supplying an effective amount for hypertensive.

DETAILED DESCRIPTION OF THE INVENTION

Most of the compounds of formulae I and Ia are prepared by the phosphitereduction of the corresponding nitroso compounds. The reduction of anitroso compound by triethylphosphite is described by J. I. Cadogan,Synthesis, 1, II (1972). The nitroso intermediates of pyridine andthiazole are prepared by condensation of an α-haloacetophenonerespectively with 2-aminopyridine and 2-aminothiazole as described byAlmirante et al., Journal of Medicinal Chemistry, 8, 305 (1968) andAlmirante et al., Journal of Medicinal Chemistry 9, 29 (1966) and thennitrosation of the resulting base with sodium nitrite and acetic acid asdescribed by La Rocca et al., Journal of Pharmaceutical Sciences, 60, 74(1971).

The preferred method of recovering the imidazoindoles from the phosphitereduction mixture is to let the mixture solidify (about 24 hoursrequired), wash with carbon tetrachloride on a glass filter andrecrystallize the residue two times from 2-propanol.

The imidazoindoles may also be recovered from the phosphite reductionmixture by allowing it to solidify, washing the solid on a glass filterwith cold carbon tetrachloride, taking the residue in a small quantityof chloroform, and eluating it over a column of activated alumina(80-325 mash). The first colored zone is collected, evaporated todryness and then recrystallized once from 2-propanol.

For the synthesis of most of imidazo-indole derivatives of my invention,known phenacyl halides or their ring substituted derivatives are usedfor condensation respectively with 2-Aminopyridines or 2-Aminothiazoles.In those isolated cases where a phenacyl halide with a desired halogensubstitution in the ring is not readily available, the desiredsubstitution in the phenyl ring is accomplished by first synthesizingthe respective tetracyclic compound without the phenyl ring substituentand later introducing the desired substituent by halogenation. Forexample: meta-halo-phenacyl halides are not readily available. Thereforethe synthesis of 4-halo-5H-pyrido [2', 1':2, 3] imidazo [4, 5-b] indolesor 6-halo-5H-thiazolo [2', 3':2, 3] imidazo [4, 5-b] indoles areachieved by subsequent halogenation of the respective unsubstitutedtetracyclic imidazo-indole derivatives.

The condensation reaction and subsequent phosphite reductions may berepresented schematically as follows: ##STR3## wherein R, R₁, R₂, R₃,are selected from the group consisting of hydrogen, halogen andlower-alkyl of from one to four carbon atoms, inclusive; with theproviso that taken together they constitute the following substituentson the tetracyclic ring, 10-halo, 8,10-dihalo, 8,9-di-lower-alkyl, and7,9-dilower-alkyl; R', R'₁, R'₂, and R'₃ are selected from the groupconsisting of hydrogen, halogen and lower alkyl of from one to fourcarbon atoms, inclusive, with the proviso that when taken together theyconstitute the following substituents on the tetracyclic ring, 1-halo,2-halo, 3-halo, 1-lower-alkyl, 2-lower-alkyl, 3-lower-alkyl, 4-loweralkyl, 1,3-dihalo, 2,3-dihalo, 2,4-dihalo, 3,4-dihalo,1,3-di-lower-alkyl, 2,3-di-lower-alkyl, 1,4-di-lower-alkyl; R₄, R₅, R₆,and R₇ are selected from the group consisting of hydrogen, halogen andlower-alkyl of from one to four carbon atoms, inclusive, with theproviso that when taken together they constitute the followingsubstituents on the tetracyclic ring, 9-halo, 8-halo, 7-halo,9-lower-alkyl, 8-lower-alkyl, 7-lower-alkyl, 6-lower-alkyl, 7,9-dihalo,7,8-dihalo, 6,8-dihalo, 6,7-dihalo, 7,9-di-lower-alkyl,7,9-di-lower-alkyl, 7,8-di-lower-alkyl, and 4,6-di-lower-alkyl. R₈ isselected from the group consisting of hydrogen, lower-alkyl of from oneto four carbon atoms, inclusive, and R₉ is selected from the groupconsisting of hydrogen and halo.

In the foregoing designation of variables, lower-alkyl means methyl,ethyl, propyl, isopropyl, butyl and the isomeric forms thereof. Halomeans chloro, bromo, iodio and fluoro.

When a pyridine derivative, the phosphite reduction is complete with15-30 minute of refluxing. Further heating yields gradual decompositionof this derivative. The thiazole derivative, formula Ia does not degradeupon prolonged heating during the reduction step.

Pharmaceutically acceptable acid addition salts of the compounds (I) areprepared by reacting a compound of formula (I) free base with astoichoimetric amount of an acid, such as hydrogen chloride, hydrogenbromide, hydrogen iodide, sulfuric acid, phosphoric acid, acetic acid,lactic acid, citric acid, succinic acid, benzoic acid, salicylic acid,pamoic acid, cyclohexanesulfamic acid, and the like.

This invention relates also to pharmaceutical dosage unit forms forsystemic administration (oral and parenteral administration) fortreating hypertensive mammals, including humans. The term "dosage unitform" as used in this specification and in the claims refers tophysically discrete units suitable as unitary dosages for mammaliansubjects, each unit containing a pre-determined quantity of theessential active ingredient, i.e., a compound (I) or a pharmaceuticallyacceptable acid addition salt thereof calculated to produce the desiredeffect in combination with the required pharmaceutical means which adaptthe said ingredient for systemic administration. Examples of dosage unitforms in accordance with this invention are tablets, capsules, orallyadministered liquid preparations in liquid vehicles, sterilepreparations in liquid vehicles for intramuscular and intravenousadministration, suppositories, and sterile dry preparations for theextemporaneous preparation of sterile injectable preparations in aliquid vehicle. Solid diluents or carriers for the solid oralpharmaceutical dosage unit forms are selected from the group consistingof lipids, carbohydrates, proteins and mineral solids, for example,starch, sucrose, kaolin, dicalcium phosphate, gelatin, acacia, cornsyrup, corn starch, talc and the like. Capsules, both hard and soft, areformulated with conventional diluents and excipients, for example,edible oils, talc, calcium carbonate, calcium stearate and the like.Liquid preparations for oral administration are prepared in water oraqueous vehicles which advantageously contain suspending agents, such asfor example, ethanol, sodium carboxymethylcellulose, acacia, polyvinylpyrrolidone, polyvinyl alcohol and the like. In the instance ofinjectable forms, they must be sterile and must be fluid to the extentthat easy syringeability exists. Such preparations must be stable underthe conditions of manufacture and storage, and ordinarly contain inaddition to the basic solvent or suspending liquid, preservatives in thenature of bactericidal and fungicidal agents, for example, parabens,chlorobutanol, benzyl, alcohol, phenol, thimerosal, and the like. Inmany cases it is preferable to include isotonic agents, for examplesugars or sodium chloride. Carriers and vehicles include vegetable oils,ethanol and polyols, for example, glycerol, propylene glycol, liquidpolyethylene glycol, and the like. Any solid preparations for subsequentextemporaneous preparation of sterile injectable preparations aresterilized, preferably by exposure to a sterilizing gas, such as forexample ethylene oxide. The aforesaid carriers, vehicles, diluents,excipients, preservatives, isotonic agents and the like constitute thepharmaceutical means which adapt the preparations for systemicadministration.

The pharmaceutical dosage unit forms are prepared in accordance with thepreceding general description to provide from about 10 mg. to about 100mg. of the essential active ingredient per dosage unit form. The amountof the essential active ingredient provided in the pharmaceutical dosageunit forms is based on my finding that the effective amount of compoundsof the invention and acid addition salts thereof, for obtaining ahypotensive effect in mammals is within a range from about 10 mg. perkg. to about 100 mg. per/kg. of body weight of the recipient, daily.

The following examples and preparations describe the manner and processof making and using the invention and set forth the best modecontemplated by the inventor of carrying out the invention but are notto be construed as limiting.

Preparation 1: 3-nitroso-2-phenylimidazo[1,2-a]pyridine

(A) A mixture of 9.5 g. of 2-aminopyridine (0.1 mole) 20 g. ofα-bromoacetophenone (0.1 mol.) and 200 ml. of 95% ethanol is refluxedfor three hours and then heated at 60° C. for an additional 12 hours.After cooling, the reaction product is condensed to a thick liquid byevaporating it in a rotary evaporator. The residue is mixed with 500 ml.of chloroform and 100 ml. of 3 N sodium hydroxide. The mixture isstirred for 10 minutes at room temperature and then separated in aseparatory funnel. The lower layer is collected, washed with 100 ml. ofwater and then evaporated. The residue is washed with two propanol on aglass filter and dried in a vacuum to yield 20 g. of2-phenylimidazo[1,2-a]pyridine.

(B) A mixture of 20 g. of 2-phenylimidazo[1,2-a]pyridine and 200 ml. ofglacial acetic acid is stirred at room temperature until the2-phenylimidazo[1,2-a]pyridine is completely dissolved. The acetic acidsolution is diluted with 20 ml. of water and cooled to 0° to 5° C. in anice-salt bath. A solution of 15 g. of NaNO₂ in 50 ml. of water is addeddropwise to the cooled acetic acid solution while the solution isconstantly stirred by a mechanical stirrer. The temperature of thesolution is kept below 5° C. during the addition of the NaNO₂ solutionand three hours thereafter. Three hours after the completion of NaNO₂additon, the reaction mixture is further stirred at room temperature for12 more hours. The green precipitate is filtered and washed thoroughlywith H₂ O on a glass filter. The residue is recrystallized once fromethanol to yield 15 g., 3-nitroso-2-phenylimidazo[1,2-a]pyridine, m.p.165°-167°.

Preparation 2: 5-nitroso-6-phenylimidazo[2,1-b]thiazole

(A) A mixture of 11 g. of 2-aminothiazole (97%, 0.1 mole) 20 g. ofα-bromoacetophenone (0.1 mol) and 200 ml. of 95% ethanol is refluxed forthree hours and then heated at 60° C. for an additional 12 hours. Aftercooling, the reaction product is condensed to a thick liquid byevaporating it in a rotary evaporator. The residue is mixed with 500 ml.of chloroform and 100 ml. of 3 N sodium hydroxide. The mixture isstirred for 10 minutes at room temperature and then separated in aseparatory funnel. The lower layer is collected, washed with 100 ml. ofwater and then evaporated. The residue is washed with two propanol on aglass filter and dried in a vacuum to yield 20 g. of6-phenylimidazo[2,1-b]thiazole.

(B) A mixture of 20 g. of 6-phenylimidazo[2,1-b]thiazole and 200 ml. ofglacial acetic acid is stirred at room temperature until the2-phenylimidazo[1,2-a]pyridine is completely dissolved. The acetic acidsolution is diluted with 20 ml. of water and cooled to 0° to 5° C. in anice-salt bath. A solution of 15 g. of NaNO₂ in 50 ml. of water is addeddropwise to the cooled acetic acid solution while the solution isconstantly stirred by a mechanical stirrer. The temperature of thesolution is kept below 5° C. during the addition of the NaNO₂ solutionand three hours thereafter. Three hours after the completion of NaNO₂addition, the reaction mixture is further stirred at room temperaturefor 12 more hours. The blueish green precipitate is filtered and washedthoroughly with H₂ O on a glass filter. The residue is recrystallizedonce from acetone to yield 12 g. of5-nitroso-6-phenylimidazo[2,1-b]thiazole, m.p. 175°-177° C.

EXAMPLE 1 Preparation of 5H-pyrido[2',1':2,3]imidiazo[4,5-b]indole

A mixture of 9.0 grams of analytically pure3-nitroso-2-phenylimidazo[1,2-a]pyridine (0.04 mol) and 10 ml. of 97%triethyl phosphite (0.05 mol) in 50 ml. of anhydrous toluene is refluxedfor 15-30 minutes with stirring and under a constant flow of drynitrogen gas. The temperature of the oil bath is kept between 110° and120° C. After cooling, the solvent and excess triethyl phosphite areremoved by vacuum distillation at 0.2 Torr. The temperature of the oilbath is kept under 120° C., also during the distillation. The residuewhich is a thick oily liquid is kept overnight at 0° C. during whichtime it solidified. The solid is washed on a glass filter with coldcarbon tetrachloride and then recrystallized twice from 2-propanol toyield 4 g. of 5H-pyrido[2',1':2,3]imidazo[4,5-b]indole, m.p. 78°-80° C.

Analysis Calc'd for: C₁₃ H₉ N₃ : C, 75.33; H, 4.34; N, 20.22. Found: C,75.17; H, 4.38; N, 20.29.

EXAMPLE 2 Preparation of1-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole

Utilizing the procedure of Example 1 and substituting3-nitroso-2-(1-methylphenyl)imidazo[1,2-a]pyridine for3-nitroso-2-phenylimidazo[1,2-a]pyridine there is obtained1-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole.

EXAMPLE 3 Preparation of3-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole

Utilizing the procedure of Example 1 and substituting3-nitroso-2-(3-chlorophenyl)imidazo[1,2-a]pyridine for3-nitroso-2-phenylimidazo[1,2-a]pyridine there is obtained3-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole.

EXAMPLE 4 Preparation of10-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole

Utilizing the procedure of Example 1 and substituting10-methyl-3-nitroso-2-phenylimidazo[1,2-a]pyridine for3-nitroso-2-phenylimidazo[1,2-a]pyridine there is obtained10-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole.

EXAMPLE 5 Preparation of8-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole

Utilizing the procedure of Example 1 and substituting8-chloro-3-nitroso-2-phenylimidazo[1,2-a]pyridine for3-nitroso-2-phenylimidazo[1,2-a]pyridine there is obtained8-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole.

Utilizing the procedures of Example 1, and substituting the appropriatenitroso compounds, the following derivatives of pyridoimidazolindole areprepared.

1-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-methyl-5H-pyrido[2,',1':2,3]imidazo[4,5-b]indole,

7-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-isopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-sec-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-t-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-bromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-bromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-bromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-bromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-bromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-bromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-bromo-5H-pyrido2',1':2,3]imidazo[4,5-b]indole,

1-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-fluoro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

9-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-iodo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1,3-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,3-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3,4-chloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1,3-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,3-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3,4-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8,10-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8,10-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7,9-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7,9-diethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7,9-dipropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7,9-diisopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

7,9-di-n-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8,9-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8,9-diethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8,9-dipropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

8,9-diisopropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1,7-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1,8-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1,9-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

1,10-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,7-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,8-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,9-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,10-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3,7-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3,8-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3,9-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

3,10-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4,7-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4,8-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4,9-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4,10-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-4-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-bromo-4-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-4-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-4-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-4-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-2,4-dimethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-2,4-diethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-2,4-dipropyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-2,4-dibutyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4,10-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4,10-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-2,4-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-bromo-2,4-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-chloro-2,4-dibromo-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

10-bromo-2,4-dichloro-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

4-chloro-9-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dichloro-9-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dichloro-9-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dichloro-9-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dichloro-9-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dibromo-9-methyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dibromo-9-ethyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dibromo-9-propyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

2,4-dibromo-9-butyl-5H-pyrido[2',1':2,3]imidazo[4,5-b]indole,

EXAMPLE 6 Preparation of 5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole

A mixture of 8.5 grams of analytically pure5-nitroso-6-phenylimidazo[2,1-b]thiazole (0.04 mole) and 10 ml. oftriethylphosphite (0.05 mole) in 50 ml. of anhydrous toluene is refluxedfor three hours with constant stirring and under a constant flow of drynitrogen. The temperature of the oil bath is kept between 110° and 120°C. After cooling, the toluene and excess triethyl phosphite are removedby vacuum distillation at 0.2 Torr. The temperature of the oil bath iskept under 120° C. also during the distillation. The residue which is athick oily liquid is kept over night at 0° C., during which time itsolidifies. The solid is washed on a glass filter with cold carbontetrachloride and then recrystallized twice from 2-propanol to yieldthree grams of 5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole.

Analysis Calc'd for: C₁₁ H₇ N₃ S: C, 61.95; H, 3.30; N, 19.70; S, 15.00.Found: C, 61.90; H, 3.34; N, 19.61; S, 15.07.

EXAMPLE 7 Preparation of7-methyl-5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole

Utilizing the procedure of Example 6 and substituting5-nitroso-6-(4-methylphenyl)imidazo[2,1-b]thiazole for5-nitroso-6-phenylimidazo[2,1-b]thiazole there is obtained7-methyl-5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole.

EXAMPLE 8 Preparation of7-chloro-5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole

Utilizing the procedure of Example 6 and substituting5-nitroso-6-(4-chlorophenyl)imidazo[2,1-b]thiazole for5-nitroso-6-phenylimidazo[2,1-b]thiazole there is obtained7-chloro-5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole.

EXAMPLE 9 Preparation of3-methyl-5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole

Utilizing the procedures of Example 6 and substituting3-methyl-5-nitroso-6-phenylimidazo[2,1-b]thiazole for5-nitroso-6-phenylimidazo[2,1-b]thiazole there is obtained3-methyl-5H-thiazole[2',3':2,3]imidazo[4,5-b]indole.

EXAMPLE 10 Preparation of2-chloro-5H-thiazolo[2',3':2,3]imidazo[4,5-b]indole.

Utilizing the procedures of Example 6 and substituting2-chloro-5-nitroso-6-phenylimidazo[2,1-b]thiazole for5-nitroso-6-phenylimidazo[2,1-b]thiazole there is obtained2-chloro-5H-thiazole[2',3':2,3]imidazo[4,5-b]indole.

Further utilizing the procedure of Example 6 and substituting theappropriate nitroso compounds, the following derivatives of thiazoloimidazoindoles are prepared

3-bromo-5H-thiazolo[2',3':2,3]imidazolo[4,5-b]indole,

7-bromo-5H-thiazolo[2',3':2,3]imidazolo[4,5-b]indole,

7,9-dimethyl-5H-thiazolo[2',3':2,3]imidazolo[4,5-b]indole,

7,9-dichloro-5H-thiazolo[2',3':2,3]imidazolo[4,5-b]indole,

7,9-dibromo-5H-thiazolo[2',3':2,3]imidazolo[4,5-b]indole,

Starting materials for preparing the nitroso-thiazoles andnitroso-pyridines of this invention are available or can be prepared bymethods described in the prior art.

I claim:
 1. A compound having the formula ##STR4## wherein R₄, R₅, R₆,and R₇ are selected from the group consisting of hydrogen, halogen andlower-alkyl of from one to four carbon atoms, inclusive, with theproviso that when taken together they constitute the followingsubstituents on the tetracyclic ring, 9-halo, 8-halo, 7-halo, 6-halo,9-lower-alkyl, 8-lower-alkyl, 7-lower-alkyl, 6-lower-alkyl, 7,9-dihalo,7,8-dihalo, 6,8-dihalo, 6,7-dihalo, 7,9-di-lower-alkyl,7,8-di-lower-alkyl and 4,6-di-lower-alkyl; R₈ is selected from the groupconsisting of hydrogen, lower-alkyl of from one to four carbon atoms,inclusive, and R₉ is selected from the group consisting of hydrogen andhalo.
 2. A compound according to claim 1 having the formula 1a andwherein R₄, R₅, R₆, R₇, R₈ and R₉ are all hydrogen, so that the specificcompound is 5-nitroso-6-phenylimidazo[2,1-b]thiazole.